Synthesis and Biological Evaluation of Novel Folic Acid Receptor-Targeted, β-Cyclodextrin-Based Drug Complexes for Cancer Treatment

Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5–2.5 nm. The host-guest association constant Ka was 1,639 M−1 as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+) cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability. The novel FA-conjugated β-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer.

Effect of pH and temperature on the carbonate promoted dissolution of sodium meta-autunite

Release of uranium from Na-autunite, an artificial mineral created as a result of polyphosphate injection in the subsurface at the DOE Hanford Site, takes place during slow dissolution of the mineral structure. Stability information of the uranyl-phosphate phases is limited to conditions involving pH, temperature, and a few aqueous organic materials. The carbonate ion, which creates very strong complexes with uranium, is the predominant ion in the groundwater composition. The polyphosphate technology with the formation of autunite was identified as the most feasible remediation strategy to sequester uranium in contaminated groundwater and soil in situ. The objectives of the experimental work were (i) to quantify the effect of bicarbonate on the stability of synthetic sodium meta-autunite created as a result of uranium stabilization through polyphosphate injection, (ii) calculate the kinetic rate law parameters of the uranium release from Na-autunite during dissolution, and (iii) to compare the process parameters with those obtained for natural calcium meta-autunite. Experiments were conducted using SPTF apparatus, which consists of syringe pumps for controlling flow rate, Teflon reactors and a heating/cooling system. 0.25 grams of synthetic Na-autunite was placed in the reactor and buffer solutions with varying bicarbonate concentrations (0.0005 to 0.003 M) at different pH (6 - 11) were pumped through the reactors. Experiments were conducted at four different temperatures in the range of 5 - 60oC. It was concluded that the rate of release of uranium from synthetic Na-autunite is directly correlated to the bicarbonate concentration. The rate of release of uranium increased from 1.90 x 10-12 at pH 6 to 2.64 x 10-10 (mol m-2 s-1) at pH 11 at 23oC over the bicarbonate concentration range tested. The activation energy values were invariant with the change in the bicarbonate concentration; however, pH is shown to influence the activation energy values. Uranyl hydroxides and uranyl carbonates complexes helped accelerate the dissolution of autunite mineral.